Total Synthesis of Maoecrystal V: Early-Stage of C-H Functionalization and Lactone

Transcription

1 Literature Report Total Synthesis of Maoecrystal V: arly-stage of C- Functionalization and Lactone Assembly by Radical Cyclization Reporter: Ji Yue Checker: Chen Muwang Date: 2013/12/02 Zakarian, A. et al. J. Am. Chem. Soc. 2013, 135, University of California at Santa Barbara

2 Content 1 Introduction 2 Retrosynthesis of Maoecrystal V 3 Synthesis of Maoecrystal V 4 Summary

3 Introduction Isodon species 毛萼香茶菜 Isolated and characterized by Sun and coworkers in 2004 Remarkably selective cytotoxicity against ela cells (IC 50 = 20 ng/ml); Cisplatin (IC 50 = 990 ng/ml). Sun,.-D. et al. rg. Lett. 2004, 6, 4327.

4 Introduction D B A C C 19 Diterpenoid Compact pentacyclic system Six stereocenters (two all-carbon) Three contiguous quaternary stereocenters

5 Introduction Yang s Synthesis The model reaction of dearomatic-diels-alder reaction Ac Pb(Ac) 4 Ac PhC D 3 o A 130 C 3 5 C Ac 92% Ac Ac 2 PhC o C 4 6 Yang, Z. et al. rg. Lett. 2009, 11, 4770.

6 Introduction o Yang s Synthesis:The first total synthesis of ( )-maoecrystal V Pb 2 (Ac) 4 Ac, 0 o C A Ac PhMe 145 o C A B C D Ac 36% yield a b c Yang, Z. et al. J. Am. Chem. Soc. 2010, 132,

7 Introduction Danishefsky s s Synthesis S 2 Ph IMDA S 2 Ph i j -face -face m-cpba p-ts k l m Danishefsky, S.-J. et al. J. Am. Chem. Soc. 2012, 134,

8 Constuction of Bicyclic [2.2.2] octane via an IMDA Reaction IMDA: Intramolecular Diels-Alder reaction t t t Cl t i-pr 2 Nt t DMAP BT, o-dcb 73% yield t 98% yield e g d Cl S Cl t 3 N, DMAP 82% yield t t f S BT, i-pr 2 Nt 60% yield t t S h Zakarian, A. et al. rg. Lett. 2011, 13, 1080.

9 Retrosynthesis of Maoecrystal V Zakarian, A. et al. J. Am. Chem. Soc. 2013, 135,

10 An arly Installation of Dihydrobenzofuran Intermediate mechanism

11 An IMDA Reaction Mechanism

12 Lactone Assembly by Radical Cyclization

13 Lactone Assembly by Radical Cyclization Bn PMB Bn PMB t-bu 3 Sn AIBN or ACN or V70 PhSe 18 (Me 3 Si) 3 Si AIBN, Ph 55% yield D 23 Bn PMB B C 19 Bn 24 Bn PMB Bn PMB step b Bn PMB step a

14 Synthesis of Maoecrystal V

15 Summary Yang's Method Wessely xidation Ac IMDA Ac Danishefsky's Method S 2 Ph IMDA S 2 Ph ( )-Maoecrystal V (1)

16 Summary

17 Among many known ent-kauranoids, maoecrystal V stands out for its atypical molecular architecture in this class of natural products. Isolated and characterized by Sun and co-workers in 2004, this unique C 19 diterpenoid displayed potent (IC 50 =20 ng/ml) and remarkably selective cytotoxicity against ela cells. The pentacyclic framework of maoecrystal V integrates three contiguous quaternary stereocenters (two all-carbon), a bicyclo[2.2.2]octan-2-one subunit, and a strained central tetrahydrofuran flanked by trans-fused six-membered rings. Collectively, these structural characteristics amount to an exquisite challenge for chemical synthesis. Numerous research groups initiated programs directed at the synthesis of maoecrystal V, identifying the construction of the quaternary stereogenic centers as one of the main strategic t goals and developing many effective solutions.

18 The successful completion of the first total synthesis of maoecrystal V in racemic form, reported by Yang and coworkers in 2010, relied on a concise strategy centered on an intramolecular Diels Alder reaction (IMDA). The reaction enables a rapid assembly of the bicyclooctanone and tetrahydrofuran ring systems in one event, albeit with low facial selectivity for the diene counterpart. The second of the two completed total syntheses of (±)-maoecrystal V reported to date was described by Peng and Danishefsky in ther research groups have also developed creative and efficient approaches based on IMDA chemistry that is envisioned to precede tetrahydrofuran formation.

19 In closing, a concise total synthesis of maoecrystal V has been accomplished (24 steps, 1.5% 1 overall yield from sesamol). The strategic focus on the central strained tetrahydrofuran ring resulted in an initial disassembly of the lactone ring to a polycyclic enol ether. The enol ether was constructed by an IMDA reaction of a tethered C 2 =C 2 equivalent with a 2,4- cyclohexadienone fragment obtained by oxidative dearomatization of a dihydrobenzofuran intermediate. This intermediate, in turn, was prepared by an effective Rhodium- catalyzed C functionalization reaction which can potentially be modified to access enantioenriched products using chiral Rhodium catalysts.

20 An IMDA Reaction Bn PMB C 3 MgBr 95% yield t Bn PMB ydrolysis MeMgBr X Mg Bn t MgX Bn MgX PMB PMB Back

21 Rh 2 (Ac) Rh -N 2 2 N 2 N 2 Rh Me Me Me Me Rh Me Rh Me Rh Me back